The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA). Prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. A challenge in achieving worldwide HIV eradication is targeting specific marginalized populations who are most likely to benefit from an HIV cure but possess poorer immune responses. For this study, HIV+ infected ART-suppressed individuals with no prior history of MA use disorder will be administered oral methamphetamine (the maximum FDA approved daily dose for the treatment of childhood obesity) to determine the effects of short-term MA exposure on residual virus production, gene expression, and inflammation. Measures of MA exposure in urine and serum will then be associated with residual virus production, gene expression, cell surface immune marker protein expression, and systemic markers of inflammation. The clinical trial data will generate advanced gene expression and immunologic data to identify potential novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapies in HIV+ individuals who use MA.

The most commonly used illicit stimulant in HIV-infected individuals is methamphetamine (MA), and prior studies demonstrate strong evidence that MA promotes increased HIV transcription as well as immune dysregulation. HIV cure has emerged as an important clinical and research priority given evidence of ongoing immune dysfunction in HIV-infected individuals despite effective antiretroviral therapy (ART). A challenge in achieving worldwide HIV eradication is targeting specific vulnerable populations who are most likely to benefit from an HIV cure but possess poorer immune responses as a result of residual viral replication due to suboptimal ART adherence and/or direct immune dysfunction from illicit substance use. Prior non-human studies demonstrate that MA directly induces HIV production and promotes immune activation and inflammation. These preclinical findings suggest that HIV+ individuals who use MA may experience greater immune dysfunction and face additional challenges for future HIV eradication. This study will investigate the effects of short-term MA exposure in HIV+ ART-suppressed individuals without a prior history of MA use. Participants will be enrolled in an interventional study where they will be administered oral methamphetamine (the maximum FDA approved daily dose for the treatment of childhood obesity) to determine the effects of short-term MA exposure on residual virus production, gene expression, inflammation, and trace amine-associated 1 (TAAR1, a promising drug target for psychostimulant addiction) signaling. MA exposure will be quantified with multiple serum samples collected over a 24-hour monitoring period and associated with residual viral transcription, host gene and cell surface protein expression, and inflammation (plasma inflammatory cytokine levels) quantification. The proposed study will be the first human genetic study to directly evaluate the effect of MA exposure on residual viral transcription during effective ART. The overall goals of the study are to integrate a rigorous clinical study designs with high throughput 'omics data to identify novel targets for reversing HIV latency, reducing inflammation, and personalizing future therapeutic strategies specific to HIV+ ART-suppressed individuals who use MA.

Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Male or female, age ≥ 18 and ≤ 65 years
3. HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load.
4. Continuous therapy with a Department of Health and Human Services (DHHS) recommended/alternative combination ART for least 24 months (at least 3 agents) at study entry with no regimen changes in the preceding 12 weeks
5. Maintenance of undetectable plasma HIV-1 RNA (<40 copies/ml) for at least 12 months. Episodes of single HIV plasma RNA 50-500 copies/ml will not exclude participation if subsequent HIV plasma RNA is <40 copies/ml.
6. No plans to modify ART during the study period (146 days, or approximately 5 months)
7. Screening CD4+ (cluster of differentiation 4) T-cell count ≥ 350 cells/mm3
8. Screening hemoglobin ≥ 12.5 g/dL
9. No current or prior history of methamphetamine (MA) use disorder by DSM-5 diagnostic criteria. Participants may have a prior history of taking prescription medications containing amphetamines-type stimulants such as Adderall® or Dexedrine® or Ritalin for the treatment of conditions such as attention deficit hyperactivity disorder as long as the participant has not taken these medications in the last 12 months or plans to take these medications during the entire study period.
10. Willingness to use two forms of contraception throughout the study period as well as up to 30 days after the last day of study completion.
11. Ability and availability to participate in the full 146 days of the study (approximately 5 month) and maintain the inclusion/exclusion criteria.

Exclusion Criteria:

1. History of methamphetamine ("meth") use disorder by DSM-5 diagnostic criteria.
2. Evidence of MA use other than due to the administered oral methamphetamine study drug, based on urine, hair, or serum MA measurements collected at baseline and follow-up study visits.
3. Current use of prescription medications containing amphetamine-type stimulants (e.g., Adderall®, Dexedrine®, Ritalin, etc.) within the last 1 year.
4. Sensitivity or allergy to amphetamine-type stimulants
5. Current use of any other "psychoactive" drug within the last 1 year. These include cocaine, ecstasy, lysergic acid diethylamide (LSD), mushrooms, or other recreational drugs - but nicotine or caffeine use is ok.
6. Marijuana use in the last 30 days; marijuana may influence the interpretation of the study drug's effect on viral transcription, inflammation, and/or gene expression.
7. Current use of opioids (heroin, methadone) or prescription opioid agonists such as hydrocodone (Norco®), buprenorphine/naloxone (Suboxone®), oxycodone (Oxycontin®), hydromorphone (Dilaudid®) within the last 1 year by self-report and/or urine qualitative screening.
8. Current use of alcohol use disorder (DSM-5 criteria) within the last 1 year as this might put patient at risk of withdrawal during the study.
9. Significant physical or psychiatric illness that might impair the ability to safely complete the study or that might be complicated by the study drugs, including prior seizures (after age 8) or other active neurological disease.
10. Clinically significant abnormalities on physical examination or screening laboratory values
11. History of serious adverse event or hypersensitivity to MA or corn starch (the latter is used in the placebo).
12. Recent use within the last month of the following medications given potential interactions with oral methamphetamine: acebrophylline, iobenguane, isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine, asunaprevir, buproprion, topical cocaine, fluoxetine, iohexol, linezolid, paroxetine, potassium citrate, quinidine, sodium bicarbonate, sodium citrate, sodium lactate, tipranavir, and tromethamine.
13. Recent hospitalization in the last 90 days.
14. Recent infection in the last 90 days requiring systemic antibiotics.
15. Screening hemoglobin below 12.5 g/dL.
16. Prior diagnosis or abnormal screening labs consistent with a diagnosis of hyperthyroidism or hypothyroidism.
17. Poorly controlled hypertension with systolic blood pressure > 160 on more than one occasion.
18. History of glaucoma.
19. Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease.
20. History of psychotic symptoms (e.g., hallucinations, delusional thinking).
21. History of bipolar disorder.
22. Significant respiratory disease requiring oxygen.
23. A history of hypersensitivity to sympathomimetic amines (e.g., epinephrine, norepinephrine, or dopamine).
24. Diabetes or current hypothyroidism.
25. Participants of reproductive potential or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at screening. All participants of childbearing potential must agree to use a double-barrier method of contraception throughout the study period and up to 90 days after the last dose of MA.
26. Exposure to any immunomodulatory drug (including maraviroc) in the 16 weeks prior to study.
27. Prior or current use of experimental agents used with the intent to perturb the HIV-1 viral reservoir.
28. History of seizures, psychosis, abnormal electroencephalogram or brain damage with significant persisting neurological deficit
29. Recent vaccination within the last 2 weeks prior to study baseline visit. Routine or standard of care vaccinations (such as influenza, pneumococcal, and meningococcal vaccinations) are allowed but must be administered greater than 14 days prior to baseline study visit.

4 months

Regular monitoring of vitals (e.g. BP, O2 levels) and ECG by MD present before and after administration of dosages on treatment days.

The order in which participants complete the two treatment phases (i.e., oral methamphetamine and placebo) will be unknown to both the participants and the PI/study team. Both the oral methamphetamine and placebo will be prepared in identical capsules by the UCSF investigational pharmacist, out of sight of the study participant, study coordinator, and study site PI and administered to the participant to maintain double blinding. The investigational pharmacist will randomize each participant according to the methods described above. In the event that participant experiences an adverse event that requires the identity of the study drug be revealed, the PI will be able to contact the investigational pharmacist to break the blind. In the event that a participant blind is broken, the study PIs will determine the impact upon the un-blinded participant's continued participation in the study and if a replacement participant is needed on a case-by-case basis.